Oxidative stress in Fanconi anaemia: from cells and molecules towards prospects in clinical management

Abstract

Fanconi anaemia (FA) is a genetic disease featuring bone marrow failure, proneness to malignancies, and chromosomal instability. A line of studies has related FA to oxidative stress (OS). This review attempts to evaluate the evidence for FA-associated redox abnormalities in the literature from 1981 to 2010. Among 2170 journal articles on FA evaluated, 162 related FA with OS. Early studies reported excess oxygen toxicity in FA cells that accumulated oxidative DNA damage. Prooxidant states were found in white blood cells and body fl uids from FA patients as excess luminol-dependent chemiluminescence, 8-hydroxy-deoxyguanosine, reduced glutathione/ oxidized glutathione imbalance, and tumour necrosis factor-α . Some FA gene products involved in redox homeostasis can be summarized as follows: (a) FANCA , FANCC , and FANCG interact with cytochrome P450-related activities and/or respond to oxidative damage; (b) FANCD2 in OS response interacts with forkhead box O3 and ataxia telangiectasia mutated protein; (c) FANCG is found in mitochondria and interacts with PRDX3, and FA-G cells display distorted mitochondria and decreased peroxidase activity; (d) FANCJ ( BACH1/BRIP1 ) is a repressor of haeme oxygenase-1 gene and senses oxidative base damage; (e) antioxidants, such as tempol and resveratrol decrease cancer incidence and haematopoietic defects in Fancd2 -/-mice. The overall evidence for FA-associated OS may suggest designing chemoprevention studies aimed at delaying the onset of OS-related clinical complications.

Binding to WGR Domain by Salidroside Activates PARP1 and Protects Hematopoietic Stem Cells from Oxidative Stress

“…To explore the clinical significance of Salidroside in HSC maintenance in a disease model, we employed the Fanconi anemia (FA) mouse model, in which oxidative stress has been identified as a physiologic mediator of HSC loss (10,29,48). To this end, we treated Fanca -/ -or Fancc -/ -mice and their Fig.…”

Proteomic analysis unveils a FANCA-modulated neddylation pathway involved in CXCR5 membrane targeting and cell mobility

“…A biallelic mutation in any of the 16 identified FANC genes causes the rare DNA damage response (DDR) syndrome Fanconi anemia. The symptoms of this syndrome include bone marrow failure, genetic instability, a predisposition to acute myeloid leukemia and head and neck cancers (Soulier, 2011), altered free radical generation and detoxification (Pagano et al, 2012), and abnormalities in cytokine production and responses (Briot et al, 2008;Pang et al, 2001;Rosselli et al, 1992). This clinical and cellular heterogeneity could result from a general disturbance of the cell and tissue metabolism as a consequence of a DDR defect, but it might also be caused by alternative activities of a single FANC protein or the existence of other currently unidentified targets of the FANCcore complex.…”

Oxidative Stress-Associated Protein Tyrosine Kinases and Phosphatases in Fanconi Anemia

“…Joenje et al later reported that chromosomal aberrations in FA were oxygen dependent (52). Since then, oxidative stress was found to modulate cell growth (26,90,91) and cycle in FA cells (26,(90)(91)(92)105) and linked to FA-associated chromosomal instability (26,52,68,90,91,100). Both in vitro and in vivo evidence indicated that FA cells were in a prooxidant state (1, 8, 11, 17, 18, 20-22, 26, 28, 37, 68, 69, 71-77, 87, 88, 90-92, 100, 103, 134).…”

“…Moreover, in the presence of genotoxic agents, such as radiation or chemotherapeutic drugs, the cytotoxic effects of TNFa can be potentiated. Overproduction of TNF-a in FA cells enhances intracellular events such as nuclear factor-jB (NFjB) activation and transcriptional activity, and leads to constitutive activation of multiple signaling pathways, including mitogen-activated protein kinase (MAPK), NF-jB (two major stress-signaling pathways), and c-Jun NH2-terminal kinase ( JNK) pathway (26,88,90,105). Furthermore, TNF-a treatment upregulated the expression of FANCA and FANCG, and increased the FANCA/FANCG complex in the nucleus as well through the NF-jB pathway (71,72) Indeed, TNF-a and its interactors have been implicated in FA pathogenesis (26,88,90,105).…”

“…Ever since early research reported excessive oxygen toxicity in FA cells, a great number of studies have related FA to oxidative stress, which has been considered a critical factor in the pathogenesis of FA (1,26,28,37,52,67,69,80,84,88,90,91,113,136,137). Oxidative stress, defined as an imbalance between the production of reactive oxygen species (ROS) and antioxidant defense, is associated with many human disease states, including FA, which is arguably a unique disease model characterized by abnormal accumulation of ROS and a dysfunctional response to oxidative damage (26,91).…”